1. Field of the Invention
This invention relates to a dissolution liquid for a drug in iontophoresis which is useful for dissolving a drug in an interface (a skin contactor or patch) for iontophoresis and delivering the drug transdermally, and a method for promoting transdermal or percutaneous absorption of the drug with the use of the dissolution liquid.
2. Description of Related Art
Iontophoresis is a system for promoting or accelerating transdermal absorption (endermic absorption) with the use of electricity as an external stimulus. The principle of such iontophoresis basically resides in promoting or enhancing transmittance of a drug molecule through a skin barrier due to, in an electric field between an anode and a cathode produced by an electric current, moving force of a positively charged molecule from the anode to the cathode, and a moving force of a negatively charged molecule from the cathode to the anode [see Journal of Controlled Release, 18, 213-220 (1992); Advanced Drug Delivery Review, 9, 119 (1992); and Pharmaceutical Research, 3, 318-326 (1986)].
Recent advances of synthetic technologies and genetic engineering insure pure and mass production of a naturally-occurring peptide or protein, or a peptide or protein in which the amino acid composition of the naturally-occurring peptide or protein is changed, or a chemically-modified derivative thereof. Therefore, application of these peptides or proteins as drugs (medicaments) have been desired. On the other hand, it has been recognized that various physiological activities are physiologically controlled by delicate and complicated in vivo kinetics with advanced researches for these peptides or proteins. Therefore, a system capable of corresponding to a strict control of administration (dosage) of these peptides or proteins is required for exhibition of the maximum drug effect in a specific disease and minimizing a side effect (adverse reaction).
By way of illustration, a calcitonin has an activity of inhibiting (suppressing) decrease of the amount of a bone by means of inhibiting bone resorption, and hence is used for treatment (therapy) of osteoporosis, Paget's disease or other diseases. Although an excessive administration of the calcitonin causes a side effect such as anorexia (inappetence), frequent administration (frequent dosage), that is, repeated administration of the calcitonin is required for promoting therapeutic effects for the disease. Further, some peptides exhibit different drug effects depending on a medication process. Taking parathyroid hormone as an example, it has been known that the parathyroid hormone has incompatible effects or activities of deossification activity and ossification promoting activity, and the deossification activity is strongly exhibited when the hormone is administered by intravenous injection at a slow rate, and ossification promoting activity is clearly expressed when the hormone is administered by frequent hypodermic injections. Accordingly, when the parathyroid hormone is used as a therapeutical drug for osteoporosis in expectation of its ossification activity, a pharmaceutical preparation comprising the hormone should be not a sustained releasable preparation but a pulse-releasable preparation.
However, such physiologically active peptide or protein is generally decomposed by a digestive fluid or juice in a gastrointestinal tract (digestive tract) or hydrolyzed by a hydrolase present in the digestive tract wall, and hence absorption efficiency of the peptide or protein can hardly be improved effectively. Therefore, sufficient drug effect of such physiologically active peptide or protein is not expected by oral administration, and it is usually administered by an injection. Administration as an injectable preparation, however, causes a great pain to a patient and burdens him with a heavy load since such injectable preparation can not be administered by himself. Still more, when repeated and continuous administration is required such as in the calcitonin or parathyroid hormone, the pain and burden of the patient are increased, particularly speaking.
In the field of pharmaceutical preparations, the iontophoresis is intensively researched as a new drug delivery system capable of corresponding to administration or delivery of such physiologically active peptide or protein. That is, development of a pharmaceutical preparation comprising a drug hitherto administrable only as an injection and being administrable by a patient himself with the use of the iontophoresis will provide a therapy at home. Further, an optional absorption pattern of a drug can be constructed by means of a precise control of an electric voltage or current application time (period). In particular, when the iontophoresis is applied supplemental therapy (treatment) of an endogenous compound in consideration of circadian rhythm of a living body, more effective therapy with it is expected to be realized.
In a drug delivery system (administration system) with the use of the iontophoresis having such advantages, an electrode for application of an electric current, a membrane holding or supporting a drug (an interface as a skin contactor or patch) which is conductible to the electrode and capable of making contact with a skin, and a reference electrode are generally employed. The drug supported by the drug-supporting membrane is dissolved with a drug dissolution liquid contained in a spacer capable of making contact with the drug-supporting membrane.
An interface for iontophoresis which comprises a drug-supporting membrane and a spacer containing a drug dissolution liquid is in a small size and has a high drug absorptivity. Use of the above interface, however, moisture content in a surface to be made contact with the skin and in the drug-supporting membrane is decreased due to transpiration or evaporation of the drug dissolution liquid during the application of the electric current, and hence electric conductivity (applicability of electric current) is deteriorated. Hence, the iontophoresis using an interface having such construction does not provide a satisfactorily sufficient transdermal drug delivery (drug absorption) with a prolonged application of the interface. Therefore, suppression of the transpiration of the dissolution liquid seems to ensure maintenance of the electric conductivity over a long period, and to provide sufficient transdermal drug delivery by means of iontophoresis.
WO 93/25168 discloses inhibition of an initial burst of transdermal absorption by using a transdermal absorbent (drug composition) containing a drug and 0.1 to 50% (v/v) of glycerin in a transdermal drug delivery system. This literature describes that the form of the drug composition is gel, cream or others, and the drug composition may comprise an adhesive for supporting the composition in a site to which the composition is applied.
WO 90/08571 discloses a drug layer of an interface for iontophoresis as produced with the use of a hard porous material or a gel, and water or a polyhydric alcohol such as glycerin as a softening plasticizer.
WO 93/10163 discloses a preparation process of a hydrophilic gel which comprises irradiating an aqueous composition comprising a crosslinkable water-soluble polymer such as a polyethylene oxide, about 1 to 40% by weight of a humectant such as glycerin or propylene glycol, and a crosslinking accelerator with a radiation. This literature also describes an application of the hydrophilic gel to a patch or an electrode assembly.
These literatures, however, fail to disclose the use of a polyhydric alcohol or an amino acid for inhibition of moisture in a dissolution liquid in the iontophoresis. Further, the use of such drug composition, drug layer or hydrophilic gel for transdermal drug administration by iontophoresis may occasionally result in an increased skin irritation accompanied with the application of an electric current.